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Mitochondria have their own tRNAs, and thecode variations do not affect the much larger cellular genomes. The most common changes in mitochondria, and the only changes observed in cellulargenomes, involve termination codons.In mitochondria, the changes can be viewed as akind of genomic streamlining.
Vertebrate mDNAshave genes that encode 13 proteins, 2 rRNAs, and22 tRNAs (see Fig. 18-29). An unusual set of wobble rules allows the 22 tRNAs to decode all 64 possible codon triplets, rather than the 32 tRNAs required for the normal code. Four codon families(where the amino acid is determined entirely bythe first two nucleotides) are decoded by a singletRNA with a U in the first (or wobble) position inthe anticodon.
Either the U pairs somehow with allfour bases in the third position of the codon, or a"two out of three" mechanism is used in these cases(i.e., no pairing occurs at the third position of thecodon). Other tRNAs recognize codons with eitherA or G in the third position, and yet others recognize U or C, so that virtually all the tRNAs recognize either two or four codons.In the normal code, only two amino acids arespecified by single codons, methionine and tryptophan (Table 26-4). If all mitochondrial tRNAs recognize two codons, then additional codons for Metand Trp might be expected in mitochondria. Hence,the single most common code variation observed isthe UGA specification, from "termination" to Trp.A single tRNA1*13 can be used to recognize and insert a Trp residue at the codon UGA and the normal Trp codon UGG.
Converting AUA from an Hecodon to a Met codon has a similar effect; the normal Met codon is AUG, and a single tRNA can beused for both codons. This turns out to be the second most common mitochondrial code variation.The known coding variations in mitochondria aresummarized in Table 1.Turning to the much rarer changes in the codesfor cellular (as distinct from mitochondrial) genomes, we find that the only known variation in aprokaryote is again the use of UGA to encode Trpresidues in the simplest free-living cell, Mycoplasma capricolum.
In eukaryotes, the only knownextramitochondrial coding changes occur in a fewspecies of ciliated protists, where the terminationcodons UAA and UAG both specify glutamine.Changes in the code need not be absolute—acodon need not always encode the same aminoacid. In E.
coli there are two examples of aminoChapter 26 Protein Metabolism907Table 1 Known variant codon assignments in mitochondriaCodons*UGAAUAAGAAGGCUNCGGNormal code assignmentStopHeArgLeuArgAnimalsVertebratesDrosophilaTrpTrpMetMetStopSer++++TYpMet+Thr+TrpMet+ThrTrp++++Filamentous fungiTrp++++TrypanosomesTrp++++Higher plants++++TrpChlamydomonasreinhardtii?+++?YeastsSaccharomycescerevisiaeTorulopsisglabrataSchizosaccharomycespombe" ? Indicates that the codon has not been observed in the indicated mitochondrial genome, N, anynucleotide, +, the codon has the same meaning as in the normal codeacids being inserted at positions not specified inthe general code.
The first is the occasional use ofthe codon GUG (Val) as an initiating codon. Thisoccurs only for those genes in which the GUG isproperly located relative to special translation initiating signals in the mRNA (as discussed later inthis chapter) that override the normal coding pattern. Thus, GUG has an altered coding specification only when it is positioned within a certain"context" of other sequences.The use of contextual signals to alter codingpatterns also applies to the second E. coli example.A few proteins in all cells (e.g., formate dehydrogenase in bacteria and glutathione peroxidase inmammals) require the element selenium for theiractivity. It is generally present in the form of themodified amino acid selenocysteine (Fig. 1). Modified amino acids are generally produced in posttranslational reactions (described later in thischapter), but in E.
coli, selenocysteine is introduced into formate dehydrogenase during translation in response to an in-frame UGA codon. A specialized type of serine tRNA, present at lower levels than other serine tRNAs, recognizes UGA andno other codons. This tRNA is charged with serine,and the serine is then enzymatically converted toselenocysteine prior to its use on the ribosome. Thecharged tRNA will not recognize just any UGAcodon; instead some contextual signal in themRNA, still to be identified, permits the tRNA torecognize only those few UGA codons that specifyselenocysteine within certain genes. In effect,there are 21 standard amino acids in E.
coli, andUGA doubles as a codon for termination and(sometimes) for selenocysteine.These variations tell us that the code is notquite as universal as once believed, but they alsotell us that flexibility in the code is severely constrained. It is clear that the variations are derivatives of the general code; no example of a completely different code has ever been found. Thevariants do not provide evidence for new forms oflife, nor do they undermine the concepts of evolution or universality of the genetic code. The limitedscope of code variants strengthens the principlethat all life on this planet evolved on the basis of asingle (very slightly flexible) genetic code.coo+ IH 3 N—CHCH 2SeFigure 1 Selenocysteine.908Part IV Information PathwaysStage 2: Initiation Next, the mRNA bearing the code for the polypeptide to be made binds to the smaller of two major ribosomal subunits;this is followed by the binding of the initiating aminoacyl-tRNA andthe large ribosomal subunit to form an initiation complex.
The initiating aminoacyl-tRNA base-pairs with the mRNA codon AUG that signals the beginning of the polypeptide chain. This process, which requires GTP, is promoted by specific cytosolic proteins called initiationfactors.Stage 3: Elongation The polypeptide chain is now lengthened by covalent attachment of successive amino acid units, each carried to theribosome and correctly positioned by its tRNA, which base-pairs to itscorresponding codon in the mRNA. Elongation is promoted by cytosolicproteins called elongation factors. The binding of each incoming aminoacyl-tRNA and the movement of the ribosome along the mRNA arefacilitated by the hydrolysis of two molecules of GTP for each residueadded to the growing polypeptide.Bacterial ribosome70SMr 2.5 x 106Eukaryotic ribosome80SMr 4.2 x 106Stage 5: Folding and Processing In order to achieve its biologicallyactive form the polypeptide must fold into its proper three-dimensionalconformation.
Before or after folding, the new polypeptide may undergo enzymatic processing to remove one or more amino acids fromthe amino terminus; to add acetyl, phosphate, methyl, carboxyl, orother groups to certain amino acid residues; to cleave the protein proteolytically; or to attach oligosaccharides or prosthetic groups.60SMr 1.6 x 1065S rRNA(120 nucleotides)23S rRNA(3,200 nucleotides)34 proteins30SStage 4: Termination and Release The completion of the polypeptidechain is signaled by a termination codon in the mRNA. The polypeptide chain is then released from the ribosome, aided by proteins calledrelease factors.Mr 2.8 x 1065S rRNA(120 nucleotides)28S rRNA(4,700 nucleotides)5.8S rRNA(160 nucleotides)~ 49 proteins40SIn our expanded discussion of these stages a particular emphasiswill be placed on stage 1.
The reason is evident on considering theoverall goal of the process: to synthesize a polypeptide chain with adefined sequence. To accomplish this task, two fundamental chemicalrequirements must be met: (1) the carboxyl group of each amino acidmust be activated to facilitate formation of a peptide bond (see Fig.5-15), and (2) a link must be maintained between each new amino acidand the information that encodes it in the mRNA. As we will see, bothof these requirements are met by attaching the amino acid to a tRNA,and attaching the right amino acid to the right tRNA is therefore critical to the overall process of protein biosynthesis.Before examining each stage in detail, we must introduce two keycomponents in protein biosynthesis: the ribosome and tRNAs.The Ribosome Is a Complex Molecular MachineMr 0.9 x 10616S rRNA(1,540 nucleotides)21 proteinsMr 1.4 x 10618S rRNA(1,900 nucleotides)~ 33 proteinsFigure 26—12 Components of bacterial and eukaryotic ribosomes.
The designation S (Svedberg units)refers to rates of sedimentation in the centrifuge.The S values (sedimentation coefficients) are notnecessarily additive when subunits are combined.Each E. coli cell contains 15,000 or more ribosomes, which make upalmost a quarter of the dry weight of the cell.
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